Neuropatía óptica de Leber: utilidad de la secuenciación masiva en el estudio de mutaciones mitocondriales en aparente homoplasmia

Salas, Pilar Carrasco; Milla, Carmen Palma; Montiel, Javier López; Benito, Carmen; Freire, Sara Franco; Siles, Juan López

doi:10.1016/j.medcli.2015.10.015

Cited by 4 publications

(2 citation statements)

References 15 publications

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“…Indeed, an increase of the mtDNA copy number in a heteroplasmic situation will modify the absolute value of the wild type mtDNA copies, even if the mutant load remains unchanged and therefore may explain the variability of the clinical phenotypes of mtDNA-related disorders, as shown for LHON (Giordano et al, 2014) or MELAS syndrome (Liu et al, 2013; Grady et al, 2018). The gain of sensitivity enabled by massive parallel sequencing also allows identifying high level of heteroplasmy, in samples that were initially considered as homoplasmic (Genasetti et al, 2007; Ballana et al, 2008; Carrasco Salas et al, 2016). The detection of heteroplasmy has always been considered as strong argument for the variant scoring pathogenicity (McFarland et al, 2004; Mitchell et al, 2006).…”

Section: Mtdna Variant Annotationmentioning

confidence: 99%

Bioinformatics Tools and Databases to Assess the Pathogenicity of Mitochondrial DNA Variants in the Field of Next Generation Sequencing

et al. 2018

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The development of next generation sequencing (NGS) has greatly enhanced the diagnosis of mitochondrial disorders, with a systematic analysis of the whole mitochondrial DNA (mtDNA) sequence and better detection sensitivity. However, the exponential growth of sequencing data renders complex the interpretation of the identified variants, thereby posing new challenges for the molecular diagnosis of mitochondrial diseases. Indeed, mtDNA sequencing by NGS requires specific bioinformatics tools and the adaptation of those developed for nuclear DNA, for the detection and quantification of mtDNA variants from sequence alignment to the calling steps, in order to manage the specific features of the mitochondrial genome including heteroplasmy, i.e., coexistence of mutant and wildtype mtDNA copies. The prioritization of mtDNA variants remains difficult, relying on a limited number of specific resources: population and clinical databases, and in silico tools providing a prediction of the variant pathogenicity. An evaluation of the most prominent bioinformatics tools showed that their ability to predict the pathogenicity was highly variable indicating that special efforts should be directed at developing new bioinformatics tools dedicated to the mitochondrial genome. In addition, massive parallel sequencing raised several issues related to the interpretation of very low mtDNA mutational loads, discovery of variants of unknown significance, and mutations unrelated to patient phenotype or the co-occurrence of mtDNA variants. This review provides an overview of the current strategies and bioinformatics tools for accurate annotation, prioritization and reporting of mtDNA variations from NGS data, in order to carry out accurate genetic counseling in individuals with primary mitochondrial diseases.

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Section: Mtdna Variant Annotationmentioning

confidence: 99%

Bioinformatics Tools and Databases to Assess the Pathogenicity of Mitochondrial DNA Variants in the Field of Next Generation Sequencing

et al. 2018

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“…The primary task is that it is not an easy job to determine a person having the mutated gene to develop the risk of optic atropy, and in secondary, not all the mutated genes in a heteroplasmic female is transferred to the next generation. [ 72 ] Also verifying the location of the mutation like homoplasmic or heteroplasmic is important in case of genetic counseling. [ 73 ]…”

Section: Therapeutics Of Leber's Hereditary Optic Neuropathymentioning

confidence: 99%

Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy

Manickam

Anto

Ramasamy

2017

Indian J Ophthalmol

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Leber's hereditary optic neuropathy (LHON) is a common inherited mitochondrial disorder that is characterized by the degeneration of the optic nerves, leading to vision loss. The major mutations in the mitochondrial genes ND1, ND4, and ND6 of LHON subjects are found to increase the oxidative stress experienced by the optic nerve cell, thereby leading to nerve cell damage. Accurate treatments are not available and drugs that are commercially available like Idebenone, EPI-743, and Bendavia with their antioxidant role help in reducing the oxidative stress experienced by the cell thereby preventing the progression of the disease. Genetic counseling plays an effective role in making the family members aware of the inheritance pattern of the disease. Gene therapy is an alternative for curing the disease but is still under study. This review focuses on the role of mitochondrial genes in causing LHON and therapeutics available for treating the disease. A systematic search has been adopted in various databases using the keywords “LHON,” “mitochondria,” “ND1,” “ND4,” “ND6,” and “therapy” and the following review on mitochondrial genetics and therapeutics of LHON has been developed with obtained articles from 1988 to 2017.

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Genetic Counselling for Maternally Inherited Mitochondrial Disorders

2017

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The aim of this review was to provide an evidence-based approach to frequently asked questions relating to the risk of transmitting a maternally inherited mitochondrial disorder (MID). We do not address disorders linked with disturbed mitochondrial DNA (mtDNA) maintenance, causing mtDNA depletion or multiple mtDNA deletions, as these are autosomally inherited. The review addresses questions regarding prognosis, recurrence risks and the strategies available to prevent disease transmission. The clinical and genetic complexity of maternally inherited MIDs represent a major challenge for patients, their relatives and health professionals. Since many of the genetic and pathophysiological aspects of MIDs remain unknown, counselling of affected patients and at-risk family members remains difficult. MtDNA mutations are maternally transmitted or, more rarely, they are sporadic, occurring de novo (~25%). Females carrying homoplasmic mtDNA mutations will transmit the mutant species to all of their offspring, who may or may not exhibit a similar phenotype depending on modifying, secondary factors. Females carrying heteroplasmic mtDNA mutations will transmit a variable amount of mutant mtDNA to their offspring, which can result in considerable phenotypic heterogeneity among siblings. The majority of mtDNA rearrangements, such as single large-scale deletions, are sporadic, but there is a small risk of recurrence (~4%) among the offspring of affected women. The range and suitability of reproductive choices for prospective mothers is a complex area of mitochondrial medicine that needs to be managed by experienced healthcare professionals as part of a multidisciplinary team. Genetic counselling is facilitated by the identification of the underlying causative genetic defect. To provide more precise genetic counselling, further research is needed to clarify the secondary factors that account for the variable penetrance and the often marked differential expressivity of pathogenic mtDNA mutations both within and between families.

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Neuropatía óptica de Leber: utilidad de la secuenciación masiva en el estudio de mutaciones mitocondriales en aparente homoplasmia

Cited by 4 publications

References 15 publications

Bioinformatics Tools and Databases to Assess the Pathogenicity of Mitochondrial DNA Variants in the Field of Next Generation Sequencing

Bioinformatics Tools and Databases to Assess the Pathogenicity of Mitochondrial DNA Variants in the Field of Next Generation Sequencing

Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy

Genetic Counselling for Maternally Inherited Mitochondrial Disorders

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